Process of preparing cholenic acid derivatives



. 2,852,933 I rnoonss F QREPARING jcHoLnNIc' ACID I a DERIVATIVES Wolter Sinit and P ieter Modderman, Oss, Netherlands,

pounds selected from the group consisting of A 3u,l 2-dihydroxy-cholenicacid and functional derivatives thereof: which compounds are intermediates in the synthesis-of adrenocortical'hormones from bile acids. It is known that the hydrogenation of A 3a-hydroxy- 12- oxo choleniqacid and the functional derivatives there- A of, can be carried out with hydrogen-in the presence of platinum as a catalyst.

Now it was found that the yield of this reduction step can bejimproved by carrying 'out thereduction-by means of an alkali metal borohydride. In addition this method has the advantage that side "reactions, which may occur in the known method with;p1atinum-as' a catalyst and in whichflhe hydroxylgroup formed in 12-position may be split ofi do not occur here.

Art-reagents "potassiumysodium', "or 'litlnumborohydride may be applied.

The present reaaaa may be carried out in an aqueous medium, in whiehicase' thef'substanceis;' brought" to solution as a salt,- ebgl asan alkali metal-salt, orin an organic solvent, such as a lower aliphatic alcohol, e. g. methanol, ethanol, isopropanol, and a butanol, or in a mixture of solvents. Preferably methanol is used.

In this reaction both the free A -3a-hydroxy-12- oxocholenic acid and functional derivatives thereof may be used as starting products.

By a functional derivative of this compound is understood an alkyl ester thereof, such as the lower alkyl esters methyl, ethyl, propyl, and pentyl ester, which may be esterified in the 3oz-p0siti0n by an aliphatic, aromatic, or araliphatic carboxylic acid, such as formic acid, acetic acid, succinic acid, benzoic acid, and fi-phenylpropionic acid.

The reaction may take place at temperatures between about 0 and 55 C. Preferably a temperature of 40 C. is applied in this hydrogenation.

It has appeared of advantage to use in this reduction about 1% mol of the reagent to 1 mol of starting substance.

After completion of the reaction the A -3u,12-dihydroxy-cholenic acid or a functional derivative thereof can be isolated from the reaction mixture nearly quantitatively, see example I. As intermediate products for the further synthesis of adrenocortical hormones they usually are not separated from the reaction mixture, however, but

directly converted into the methyl-A 3 a,9a-epoxy-cholenate which is brominated to the corresponding, 11,12-dibromocompound, which is obtained in the form of two stereo-isomers, viz. the 11fi,12a-dibromocompound melting at 143 C. and the 11a,12fl-dibromocompound melting at 123 C.

The total yield of the said dibromides, calculated on the starting product of this reaction series, amounts to 115 to 120%, whereas according to the known method of hydrogenating a yield of about 105% can be obtained. The high-melting dibromide is applied for further syn- ,12' thesis'ythe low-melting isomercan beconvertedinto the high-melting form.

EXAMPLE I A -3u,12-dihydroxych0lenic acid 7 In'500 ml. of distilled water, in which 115g". of sodium hydroxide have been dissolved, 'l00 g. of"A -3oc'-hydroxy12-oxocholenic acid are =brought=iat 'room temperature, while stirring. 15 g. of sodium borohydride are added. After stirring for about 20 minutes a' voluminous precipitate is formed which disappears again. After 1 hour the temperature of the solution is raised to 40 -C. After 12 hours the reduction is completed. The reaction mixture is added dropwise to-a solution of 2 0 ml. ofconcentrated sulphuric acid in 500 mLof water while stirring. v I g V The resulting, precipitated A -3u,12-dihydroxy?cholenic acid is filtered by suction and washedwith water. After drying 99 g. of aproduct are obtained whichrepresent a mixture of ta -3a,12u-dihydroxy-cholenic acid and of-the corresponding 302,12/3-dihYdl0XY compound which are both considered for further processing.

" EXAMPLE II 8.2 g. of potassium borohydride are added, while' s'tir- -r'ing,to a':soluti'on of 50g. of methyl-a ofibenzyloxy- "l2-'oxo-'cholenate in mixture 'of 25O ml. of 'e'thanoland 150 ml. of water. The mixture is heated to 35*-C.-aud stirred at this temperature for 10 hours. Subsequently the reaction mixture is evaporated to nearly dry, after which" the :"re'sidue is 5 dissolved, while heating-"in 250 ml. ot petroleum ether. 'Aftercooling this etherealsolution,

= the methyl "ester of the A -3it-benzylo'xy lZ-hydroxy- -"cholenic 1 acid 1 crystallizes, 'which 3 compound is then separated.

In the same manner other functional derivatives of the A -3a-hydroxy-12-oxo ch0lenic acid are reduced, such as the methyl-A -3u-acetoxy-12-oxo-cholenate; the ethyl-A -3a-benzoxy-12-oxo-cho1enate; the ethyl-A 3u-succinyloxy-12-oxo-cholenate, and the prowl-A 3oc-propionoxy-12-oxo-cholenate, as a result of which the corresponding 12-hydroxy compounds are formed.

EXAMPLE III M ethyl-A (11) -3 oc,1 Z-dihydroxychOlenate 100 g. of A -3u-hydroxy-12-oxo-cholenic acid are dissolved in 600 ml. of methanol, .after which a solution of 11.5 g. of sodium hydroxide in 15 ml. of water and m1. of methanol are added. Then 10 g.- of sodium borohydride are added while stirring. The mixture is brought to 40 C. and stirred :at this temperature for 4 hours.

The formed M -3a-12-dihydroxy-cholenic acid is directly processed further to the methyl-A -3u-hydroxy- 12-methoxycholenate. For that purpose 45 ml. of concentrated sulphuric acid in ml. of methanol are added dropwise to the resulting solution, while stirring. The formed suspension is heated at 4045 C. for 4 hours. To neutralize the sulphuric acid subsequently g. of sodium acetate 3 aq. are added. Subsequently the mixture is diluted with 5 l. of water and the methyl-A 3a-hydroxy-12-methoxy-cholenate is extracted with chloroform. The extract is evaporated to a volume of 400 ml.

Methyl-A den,9oz-ep0xych0lenate V The chloroform solution of the methyl-A -3a-hydroxy-lZ-methoxy-cholenate is stirred with 300 ml. of concentrated hydrochloric acid at -10 C. for 4 hours. The methyl-A -3a-hydroxy -12 chloro-ch0lenate is formed. Subsequently the chloroform layer is separated.

layers are evaporated to 240 ml.

M ethyl-3a,9a-epoxy-1 1 ,1 Z-a'ibromocholanate 25 m1. of bromine are dissolved, while stirring, in l l. of dry chloroform which had been cooled to 30 C. The solution is further cooled to -60" C. To this is added, while stirring, the chloroform solution of the methyl-A 6 a,9a-epoxy-cholenate likewise cooled to 60 C. The mixture is stirred for 90 minutes, after which it is poured into a solution of 45 g. of sodium bicarbonate and 45 g. of sodium sulphite in 1.250 ml. of water. After discolouring the chloroform layer, the latteris separated-and washed with water till neutral reaction. After drying and evaporating the chloroform solution to 180 ml. 620 ml. of methanol are added, while stirring, in

, which crystallisation of the desired final product takes cholenic acid, lower alkyl esters and esterified 3d-hydmxy derivatives thereof with an alkalimetal borohydride.

2. A method of preparing compounds selected from the group consisting of A -3u,12-dihydroxy-cholenic acid, lower alkyl esters and esterified 3a-hydroxy derivatives thereof, which comprises, reducing a compound selected from the group consisting of A -3-hydroxy-12-oxocholenic acid, lower alkyl esters and esterified Sa-hydroxy derivatives thereof with an alkali metal borohydride .in methanol as solvent.

3. A method of preparing compounds selected from the group consisting of A -3a,IZ-(lihYdIOXY-Ci'lOlCllic acid, lower alkyl esters and esterified 3a-hydroxy derivatives thereof, which comprises, reducing a compound selected from the group consisting of A -3a-hydroxy-l2-oxocholenic acid, lower alkyl esters and esterified 3a-hydroxy derivatives thereof with an alkalimetal borohydride at a temperature of about C. 1

4. A method of preparing compounds selected from the group consisting of A -3u,12 dihydroxy-cholenic acid, lower alkyl esters and esterified 3a-hydroxy derivatives thereof, which comprises, reducing a compound selected from the group, consisting of A -3at-hydroxy- 12-oxo-cholenic acid, lower alkyl esters and esterified 3a-hydroxy derivatives thereof with about 1.5 mols of an alkali metal borohydride to each mol of the starting substance.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Shoppe et al.: Chem. & Ind. (1954), 311. Zorbach: I. A. C. S. 75, 63445 

1. A METHOD OF PREPARING COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF *9(11)-3A, 12-DIHYDROXY-CHLOLENIC ACID, LOWER ALKYL ESTERS AND ESTERIFIED 3A-HYDROXY DERIVATIVES THEREOF, WHICH COMPRISES REDUCING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF *9(11)-3A-HYDROXY-12-OXOCHOLENIC ACID, LOWER ALKLY ESTERS AND ESTERIFIED 3A-HYDORXY DERIVATIVES THEREOF WITH AN ALKALI METAL BOROHYDRIDE. 